The present invention relates to a novel polypeptide (BCMP 101) compositions comprising the polypeptide, including vaccines, and antibodies that are immunospecific for the polypeptide. The use of the polypeptide in the diagnosis, prophylaxis and treatment of cancer, in particular breast cancer is also provided.
Breast Cancer
Breast cancer is the most frequently diagnosed non-skin cancer among women in the United States. It is second only to lung cancer in cancer-related deaths. In the UK, breast cancer is by far the commonest cancer in women, with 34,600 new cases in 1998 (Cancer Research Campaign). Ninety-nine percent of breast cancers occur in women. The risk of developing breast cancer steadily increases with age; the lifetime risk of developing breast cancer is estimated to be 1 in 8 for women in the US. The annual cost of breast cancer treatment in the United States is approximately $10 billion (Fuqua, et. al. 2000, American Association for Cancer Research, USA). Breast cancer incidence has been rising over the past five decades, but recently it has slowed. This may reflect a period of earlier detection of breast cancers by mammography. A number of established factors can increase a woman's risk of having the disease. These include older age, history of prior breast cancer, significant radiation exposure, strong family history of breast cancer, upper socioeconomic class, nulliparity, early menarche, late menopause, or age at first pregnancy greater than 30 years. Prolonged use of oral contraceptives earlier in life appears to increase risk slightly. Prolonged postmenopausal oestrogen replacement increases the risk 20 to 40%. It has been speculated that a decrease in the age at menarche, changing birth patterns, or a rise in the use of exogenous estrogens has contributed to the increase in breast cancer incidence (Fuqua, et. al. 2000, American Association for Cancer Research, USA).
Causes of Breast Cancer
Breast cancer is a heterogeneous disease. Although female hormones play a significant role in driving the origin and evolution of many breast tumours, there are a number of other recognised and unknown factors involved. Perturbations in oncogenes identified include amplification of the HER-2 and the epidermal growth factor receptor genes, and over-expression of cyclin D1. Over-expression of these oncogenes has been associated with a significantly poorer prognosis. Similarly, genetic alterations or the loss of tumour suppressor genes, such as the p53 gene, have been well documented in breast cancer and are also associated with a poorer prognosis. Researchers have identified two genes, called BRCA1 and BRCA2, which are predictive of pre-menopausal familial breast cancer. Genetic risk assessment is now possible, which may enhance the identification of candidates for chemoprevention trials (Fuqua, et al. 2000, American Association for Cancer Research, USA).
Diagnosis
Early diagnosis of breast cancer is vital to secure the most favourable outcome for treatment. Many countries with advanced healthcare systems have instituted screening programs for breast cancer. This typically takes the form of regular x-ray of the breast (mammography) during the 50-60 year old age interval where greatest benefit for this intervention has been shown. Some authorities have advocated the extension of such programs beyond 60 and to the 4049 age group. Health authorities in many countries have also promoted the importance of regular breast self-examination by women. Abnormalities detected during these screening procedures and cases presenting as symptomatic would typically be confirmed by aspiration cytology, core needle biopsy with a stereotactic or ultrasound technique for nonpalpable lesions, or incisional or excisional biopsy. At the same time other information relevant to treatment options and prognosis, such as oestrogen (ER) and progesterone receptor (PR) status would typically be determined (National Cancer Institute, USA, 2000, Breast Cancer PDQ).
Disease Staging and Prognosis
Staging of breast cancer is the key to choosing the optimum treatment for each patient and to select those patients who will fare well with less intensive forms of therapy from those for whom intensive therapy is essential. Currently the process of staging involves lump and axillary lymph node biopsies, combined with extensive histopathology. Patients can be incorrectly staged with consequent over- or under-treatment. As such, there is a need for new markers that can be correlated with disease stage and used to reliably guide treatment decisions. Such new markers would not only benefit patients and health care providers by selecting the optimum treatment, but could provide significant cost and time benefits in the histology lab.
Some breast tumours become refractory to treatments, as the cancer cells develop resistance to chemotherapy drugs or lose their hormone sensitivity, leading to recurrent or metastatic disease which is often incurable. More recently, attention has focussed on the development of immunological therapies, (Green, M. C., et al. Cancer Treat. Rev. 26, 269-286 (2000); Davis, I. D., et al. Immunol. Cell Biol. 78, 179-195 (2000); Knuth, A., et al. Cancer Chemother Pharmacol. 46, S46-51 (2000); Shiku, H., et al. Cancer Chemother. Pharmacol. 46, S77-82 (2000); Saffran, D. C., et al. Cancer Metastasis Rev. 18, 437449 (1999)), such as cancer vaccines and monoclonal antibodies (mAbs), as a means of initiating and targeting a host immune response against tumour cells. In 1998 the FDA approved the use of Herceptin™ (Stebbing, J., et al. Cancer Treat. Rev. 26, 287-290 (2000); Dillman, R.O. Cancer Biother. Radiopharm. 14, 5-10 (1999); Miller, K. D., et al. Invest. New Drugs 17, 417427 (1999)), a mAb that recognises the erbB2/HER2-neu receptor protein, as a treatment for metastatic breast cancer. In combination with chemotherapy, Herceptinm™ has been shown to prolong the time to disease progression, when compared to patients receiving chemotherapy alone (Baselga, J., et al. Cancer Res. 58, 2825-2831 (1998)). Herceptinm™, however, is only effective in treating the 10-20% of patients whose tumours over-express the erbB2 protein. Thus, the identification of other suitable targets or antigens for immunotherapy of breast cancer has become increasingly important.
An ideal protein target for cancer immunotherapy should have a restricted expression profile in normal tissues and be over-expressed in tumours, such that the immune response will be targeted to tumour cells and not against other organs. In addition, the protein target should be exposed on the cell surface, where it will be accessible to therapeutic agents. Tumour antigens have been identified for a number of cancer types, by using techniques such as differential screening of cDNA (Hubert, R. S., et al. Proc. Natl. Acad, Sci. USA 96, 14523-14528 (1999); Lucas, S., et al. Int. J. Cancer 87, 55-60 (2000)), and the purification of cell-surface proteins that are recognised by tumour-specific antibodies (Catimel, B., et al. J. Biol. Chem. 271, 25664-25670 (1996)). Proteomics may be used as an alternative approach to identifying breast tumour antigens (EP 1208381, EP 1159618).
The present invention is based on the identification of a novel protein (BCMP 101) as a target for cancer therapy and diagnosis.
BCMP 101 was identified and cloned from MDA-MB468 breast cancer cell membranes. Expression of BCMP 101 in normal human tissue showed that the highest levels of expression were found in mammary, kidney and bladder tissue. Expression of BCMP 101 was elevated in kidney cancer cell lines in comparison to normal tissues. Furthermore, elevated levels of BCMP 101 gene expression were also observed in tumour tissue from a set of seven matched normal and tumour samples from breast cancer patients. The BCMP 101 sequence (FIG. 1, SEQ ID NO: 1) matches GenBank entry CAD 10629—NSE2 protein [Homo sapiens]—a Povel NS-containing protein), which was published after the priority date of this application.